tbuckley/cabot-search huggingface dataset:
Abstract 3287: A bedside to bench study of anti-PD-1, anti-CD40, and anti-CSF1R indicates that more is not necessarily better
Authors: Dijana Djureinovic, Sarah A. Weiss, Irina Krykbaeva, Rihao Qu, Ioannis Vathiotis, Myrto Moutafi, Lin Zhang, Ana L. Perdigoto, Wei Wei, Gail Anderson, William Damsky, Michael Hurwitz, Barbara Johnson, Amit Mahajan, Frank Hsu, Kathryn Miller-Jensen, Yuval Kluger, Mario Sznol, Susan M. Kaech, Marcus Bosenberg, Lucia Jilaveanu, Harriet M. Kluger
Journal: Cancer Research (2023)

Abstract Stimulating innate immunity can potentially enable us to overcome resistance to PD-(L)1 blockade. We previously conducted a phase 1 trial of cabiralizumab (anti-CSF1R) with sotigalimab (CD40 agonistic antibody) and nivolumab. Our purpose was to determine safety and the effects of this regimen on circulating and tumor-infiltrating immune cells and to determine the activity of this regimen in a phase 1b trial for melanoma patients whose disease had progressed on anti-PD-(L)1. CyTOF analysis on circulating immune cells taken before and during treatment revealed a reduction in non-classical monocytes and an increase in dendritic cells. Patients with prolonged stable disease had less T-regulatory cells and more circulating antigen presenting cells after treatment compared to patients that were treated for a shorter time. In the phase 1b component of the trial in 13 melanoma patients, objective response rates were: 1 confirmed partial response (7.7%), 1 unconfirmed partial response (7.7%), 5 stable disease (38.5%) and 6 disease progression (42.6%). Despite therapy-induced changes in circulating immune cells and previous preclinical studies supporting rationale for this combination, responses in humans were insufficient to proceed to the second stage of the phase 1b trial. Given the challenges with translating doses from mice to humans, we proceeded to study various doses of anti-CSF1R in combination with CD40 agonist and anti-PD-1 in a murine model. Higher dose anti-CSF1R in mice was associated with increased tumor growth, worse survival and by single-cell RNA-sequencing analyses, we identified a more suppressive monocyte/macrophage profile in murine tumors. Our study suggests that more anti-CSF1R might not be better. Further optimization of cabiralizumab dosing is necessary to evaluate the clinical potential in combination with anti-PD-1 and anti-CD40 in a difficult-to treat patient population whose therapeutic options are limited. Citation Format: Dijana Djureinovic, Sarah A. Weiss, Irina Krykbaeva, Rihao Qu, Ioannis Vathiotis, Myrto Moutafi, Lin Zhang, Ana L. Perdigoto, Wei Wei, Gail Anderson, William Damsky, Michael Hurwitz, Barbara Johnson, Amit Mahajan, Frank Hsu, Kathryn Miller-Jensen, Yuval Kluger, Mario Sznol, Susan M. Kaech, Marcus Bosenberg, Lucia Jilaveanu, Harriet M. Kluger. A bedside to bench study of anti-PD-1, anti-CD40, and anti-CSF1R indicates that more is not necessarily better [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3287.
Abstract 2485: RAB31 interacts with AGR2 to respond to oxaliplatin resistance and epithelial-mesenchymal transition in colorectal cancer cells via the EGFR-independent pathway
Authors: Chi-Long Chen, Michael Hsiao
Journal: Cancer Research (2023)

Abstract In the process of colonic epithelial carcinogenesis, the epithelial-mesenchymal transition may occur and bring metastatic ability and drug resistance. These events will affect patient outcomes and clinical treatment strategies. To this end, we investigated differentially expressed genes between several chemotherapy regimens in colon cancer cells through available transcriptomics datasets. We identified a member of the Rab family, RAB31, which is overexpressed after oxaliplatin treatment, while the other option is not (Irinotecan). We confirmed that RAB31 can enhance resistance to oxaliplatin in some overexpression models and that RAB31 has the ability to promote exocytosis and vesicle trafficking. Using shRNA as complementary models, we observed consistent trends when RAB31 function was discarded. Moreover, our evidence determined epithelial-mesenchymal transition (EMT)-related molecules responsive in the RAB31 bidirectional models, including CDH2, SNAI1, SNAI2 and TWIST1. The expression of RAB31 has an independent prognostic value in patients with colon cancer and is significantly positively correlated with mesenchymal markers. Furthermore, the interactome analysis selected RAB31 and AGR2 to form a direct protein interaction. This result differs from previous studies that did not rely on EGFR binding and signaling. Taken together, our study found that RAB31 can modulate oxaliplatin sensitivity and EMT status, which are additional chemotherapeutic strategies and independent prognostic factors for the treatment of colorectal cancer. Citation Format: Chi-Long Chen, Michael Hsiao. RAB31 interacts with AGR2 to respond to oxaliplatin resistance and epithelial-mesenchymal transition in colorectal cancer cells via the EGFR-independent pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2485.
Abstract 5959: Dissecting the stromal drivers of gastroesophageal adenocarcinoma chemoresistance
Authors: Kulsum Tai, Sanjima Pal, Julie Bérubé, Iris Kong, Adam Hoffman, Swneke Bailey, Aki Kirbizakis, Sui Huang, Michael Strasser, David Gibbs, Nicholas Bertos, Veena Sangwan, Lorenzo Ferri
Journal: Cancer Research (2023)

Abstract Gastroesophageal adenocarcinoma (GEA) is the fastest rising cancer in North America. Over the course of five years, the survival rate is &amp;lt;20%, creating an urgent need for appropriate treatments against GEA. Currently, providing patients with peri-operative systemic docetaxel triplet-based chemotherapy (DCF or FLOT) is the most effective approach to treat GEA. Despite this, for 50% of patients that do present an initial response to therapy, the tumor returns due to pre-existing or newly acquired resistance (i.e., chemoresistance) by the cancer. Researchers have shifted their focus to the tumor microenvironment (TME) as one of the factors influencing chemoresistance in patients. The TME is composed of tumor cells, immune cells and their secreted products, as well as fibroblasts. The components of the TME have been shown to interact with one another to influence tumor growth and progression. Fibroblasts are wound-healing cells that can be transformed into cancer-associated fibroblasts (CAFs) in response to stress and the release of inflammatory products. CAFs are the most abundant cells in the TME, yet their role in the chemoresponse of GEA is still unclear. Previous studies on other cancer types demonstrated that CAF expression is distinct between chemoresistant and chemo-sensitive tumors and certain CAF subpopulations may confer this resistance. This project will investigate the role of CAFs in the chemo-response of GEA using patient-derived organoids (PDOs) and CAFs from &amp;gt;200 GEA patients. A single-cell RNA sequencing atlas developed from &amp;gt;30 GEA DCF- or FLOT-treated patient samples will be used to identify CAF markers and targetable processes. CAF sub-populations will then be elucidated and correlated to tumor response. IF, FACS, and ELISA will be performed for subsequent CAF marker validation and characterization. Ex vivo drug testing with DCF or FLOT will be conducted on PDO-CAF co-cultures to recapitulate their drug response. Citation Format: Kulsum Tai, Sanjima Pal, Julie Bérubé, Iris Kong, Adam Hoffman, Swneke Bailey, Aki Kirbizakis, Sui Huang, Michael Strasser, David Gibbs, Nicholas Bertos, Veena Sangwan, Lorenzo Ferri. Dissecting the stromal drivers of gastroesophageal adenocarcinoma chemoresistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5959.
Abstract 6126: Antitumor effect of Iso-mukaadial acetate in MCF-7 human cancer xenograft models
Authors: Portia Raphela-Choma, Lesetja R. Motadi, Mpho S. Choene
Journal: Cancer Research (2023)

Abstract Antitumor drugs used today have shown significant efficacy and are derived from natural products such as plants. Iso-mukaadial acetate has previously been shown to possess anticancer properties by inducing apoptosis. The purpose of this study was to investigate the therapeutic effect of Iso-mukaadial acetate in the breast cancer xenograft mice model. Female athymic mice were used and were inoculated with breast cancer cells subcutaneously after culturing. Group one served as a negative control group (no treatments) and group two positive control group (cisplatin) which was administered intravenously. Iso-mukaadial acetate treatment was administered orally to group three(100 mg/kg) and group four (500 mg/kg). Blood was collected (70 µL) from the tail vein on day zero, day seven and day 14. Tumor regression was measured, and a pharmacokinetic study was conducted. Estimation of Serum Parameters for Hepatic and Renal Indices were examined using an Automated Chemistry Analyzer. Histopathological analysis was conducted to evaluate morphological changes before and after treatment under a light microscope. Tumor shrinkage was observed after treatment. In conclusion, Iso-mukaadial acetate inhibited tumor progression in breast cancer athymic mice without major side effects. Citation Format: Portia Raphela-Choma, Lesetja R. Motadi, Mpho S. Choene. Antitumor effect of Iso-mukaadial acetate in MCF-7 human cancer xenograft models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6126.
Abstract 6577: CARMEN: A pan-HLA and pan-cancer proteogenomic database on antigen presentation to support cancer immunotherapy
Authors: Ashwin Adrian Kallor, Michał Waleron, Georges Bedran, Patrícia Eugénio, Catia Pesquita, Daniel Faria, Fabio Massimo Zanzotto, Christophe Battail, Ajitha Rajan, Javier Alfaro
Journal: Cancer Research (2023)

Abstract Cancer immunotherapy has greatly improved the quality of life of cancer patients and it hinges on the discovery of novel cancer antigens that could be targeted to improve disease outcomes. The creation of databases such as IEDB, SysteMHC, TANTIGEN, caAtlas, HLA Ligand Atlas, Cancer Antigenic Peptide Database, SPENCER and IEAtlas support the immunopeptidomics community in understanding the landscape of antigen presentation. We have developed a pan-cancer, pan-HLA, and pan-tissue database containing immunopeptidomics data mapped to transcriptomic, genomic, immunological and biochemical data. The database was generated from 80 different publicly available immunopeptidomics mass spectrometry datasets collected between 2015-2022 (76 cancer and 4 normal datasets), covering 15 different types of cancers and 152 different HLA-I alleles. The peptides contained in our database were obtained by a combination of closed, open and de novo searches using an in-house developed computational pipeline. Following rigorous false discovery rate estimation at 1% and a second-round search to eliminate any false signals that may not have been detected in the previous round of FDR estimation, we obtained a list of 11.2 million peptide-HLA combinations comprising both coding and non-coding regions of the genome as well as bacterial peptides. These peptides have been mapped to chromosomal coordinates to facilitate adoption by the genomics community of this useful resource on antigen presentation. Pathway/biochemical analysis of each peptide was performed using the rWikiPathways package. Finally, mutations associated with each peptide were annotated using COSMIC and dbSNP resources. Our database includes a FAIR knowledge graph which contextualizes and enriches the data to enable clinicians to take effective therapeutic decisions on the appropriate form of treatment for cancer immunotherapy with the case study of clear cell renal cell carcinoma (ccRCC). We will continue to expand our database with new data over the next two years and expand the scope of its applications to facilitate uptake by the larger scientific community. Citation Format: Ashwin Adrian Kallor, Michał Waleron, Georges Bedran, Patrícia Eugénio, Catia Pesquita, Daniel Faria, Fabio Massimo Zanzotto, Christophe Battail, Ajitha Rajan, Javier Alfaro. CARMEN: A pan-HLA and pan-cancer proteogenomic database on antigen presentation to support cancer immunotherapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6577.
Abstract 6779: Spatial and single-nucleus transcriptomics of human glioblastoma
Authors: Yue Hao, Angela Baker, Brian Hilbush, Marcos Otero, Chris Streck, Karen L. Fink, George J. Snipes, Bruce E. Mickey, Michael Berens
Journal: Cancer Research (2023)

Abstract Glioblastoma (GBM) multiforme is the most aggressive type of brain cancer. These lethal brain tumors are characterized by the inter- and intra-tumor molecular heterogeneity and diverse cell plasticity. We sought to interrogate the immune landscape of GBM, tease out the distinct biological and therapeutic niches in GBM and to understand how the tumor microenvironments mediated the heterogeneity of GBM. We have collected six human GBM samples for spatial profiling and single-nucleus RNA sequencing. Multiple sets of spatial gene panels were designed to capture the cell identities (cancer stem cells, astrocytes, oligodendrocytes, microglia, macrophages, endothelial cells, etc.) and the spatially-resolved expression patterns of genes indicative of different functional states. We also aim to find altered neurovascular units by examining the spatial correlation between cells that highly express angiogenesis markers such as VEGFA with tumor-associated macrophages, which could be recruited to the angiogenic niche by GBM tumor cells. From the spatial RNA dataset of the first two samples, we observed close proximity of tumor-associated macrophages and endothelial cells that form the microvasculature. Our preliminary results from the single-nucleus RNA sequencing and spatial transcriptomics of two samples shed light on the complex cell landscape and the dynamic interaction between tumor cells and infiltrating or resident immune cells in the GBM tumor tissue. Citation Format: Yue Hao, Angela Baker, Brian Hilbush, Marcos Otero, Chris Streck, Karen L. Fink, George J. Snipes, Bruce E. Mickey, Michael Berens. Spatial and single-nucleus transcriptomics of human glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6779.
Abstract 2846: The mitochondrial dynamics of breast cancer regulate P-glycoprotein expression
Authors: David Terrero, Saloni Malla, Dayanidhi Raman, Jayachandra Babu, Amit Tiwari
Journal: Cancer Research (2023)

Abstract Multidrug efflux transporter ABCB1 (MDR1) encodes P-glycoprotein (P-gp), a well-known transporter that is believed to contribute to the development of multidrug resistance (MDR). Furthermore, P-gp plays an important role in drug disposition, pharmacokinetics, and drug development. Thus, P-gp transporter expression, function, and modulation of MDR in human cancers have been extensively studied. In spite of significant progress in understanding P-gp, ABCB1 regulation and its impact on clinical trials remain unclear. Through sequential exposure of SUM159PT to paclitaxel, we created a paclitaxel resistant triple negative breast cancer cell line SUM159PT-PAC200. We observed a significant increase in the phosphorylation of the mitochondrial fission protein dynamin related protein kinase 1 (Drp1) at Ser616 and its upstream kinase ERK1/2a of Drp1. Through the use of CRISPR-Cas9 technology, we knocked out the gene encoding Drp1 in PAC200. When Drp1 is genetically abated (PAC200 Drp1-/-), paclitaxel resistance is significantly reversed. It was also observed that clonogenicity under paclitaxel pressure was significantly decreased in both the PAC200/Drp1-/- line and the partial KO Drp1-/+ line, compared to the PAC200 line. Parallelly, a significant increase in the expression of P-gp transporters was also observed in the PAC200 cell line. As a surprise, genetically targeting Drp1 in PAC200 cells (i.e., PAC200 Drp1/KO) reduced P-gp expression to virtually undetectable levels. Until now, there has been no description of how Drp1 and P-gp are related. Furthermore, PAC200 Drp1/KO cells showed reduced proliferation, migration, and invasion potential, while their soft agar clonogenic capacities were almost nonexistent, suggesting that Drp1 plays a key role in breast cancer proliferation and dissemination. It appears that modulating or targeting Drp1 might be a useful strategy for modulating P-gp in the development and maintenance of the cancer's MDR phenotype, proliferation, and invasion. Understanding how mitochondrial dynamics determine the transactivation and coordination of drug-resistant P-gp phenotypes would make Drp1 an attractive molecular target for cancer treatment. Citation Format: David Terrero, Saloni Malla, Dayanidhi Raman, Jayachandra Babu, Amit Tiwari. The mitochondrial dynamics of breast cancer regulate P-glycoprotein expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2846.
Abstract 4634: Identifying and analyzing tumor subtypes using custom morphology markers for NanoString® GeoMx® Digital Spatial Profiler
Authors: Jessica Runyon, Vijay Baichwal, Weston Stauffer, Christian Nievera
Journal: Cancer Research (2023)

Abstract Molecular subtyping studies have allowed the allocation of cancer into groups based on similar molecular, morphological, and clinical characteristics. Such studies are critical to help researchers identify actionable targets for drug design and biomarkers to predict therapeutic response. Based on multi-omics data, various approaches have been used to identify and analyze tumor subtypes and their correlation with tumor immunity and immunotherapy success. The NanoString GeoMx Digital Spatial Profiler is one approach that combines morphological context with spatial transcriptomics on a single tissue specimen. A critical step in this approach involves staining with morphology markers to identify relevant regions of interest (ROIs) for analysis. Yet, widespread adoption of GeoMx DSP has revealed a significant limitation, namely that researchers base transcriptional analysis of thousands of RNA targets on the spatial information provided by only a few morphology markers. Recent efforts have greatly expanded the availability of morphology markers to facilitate cell type-specific analyses. To evaluate the ability of this technology to selectively enrich specific cell types, we developed custom morphology markers to stain non-small-cell lung cancer (NSCLC) tissue specimens of various subtypes. Focusing on squamous cell carcinoma and adenocarcinoma, we stained with P40 and TTF-1 and transcriptionally profiled cell type-specific ROIs with the Cancer Transcriptome Atlas panel. Differential gene expression analysis of the whole transcriptome was performed using GeoMx DSP Analysis Suite software. The data reveal differences in gene expression in several key cancer pathways between tumor subtypes are correlated with the presence or absence of specific cell types. The data support the use of custom morphology markers for cell type stratification in tumor subtypes, providing more meaningful gene expression analysis. Ongoing work continues to explore the utility of this technology for cell type-specific gene expression analysis within different tumor subtypes. Citation Format: Jessica Runyon, Vijay Baichwal, Weston Stauffer, Christian Nievera. Identifying and analyzing tumor subtypes using custom morphology markers for NanoString® GeoMx® Digital Spatial Profiler. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4634.
Abstract 4075: A modified FcγRI expressing-T cell, SolidT, enables antibody-mediated cytotoxicity to overcome the limitations of CAR-T cell therapy against solid tumors
Authors: Diana Rasoulouniriana, Nadine Santana-Magal, Amit Gutwillig, Leen Farhat-Younis, Hana Shpilt, Shahar Dotan, Noam Pilpel, Peleg Rider, Yaron Carmi
Journal: Cancer Research (2023)

Abstract The pioneering design of chimeric antigen receptor T-cell (CAR-T) therapy demonstrated the potential of reprogramming the immune system. Nonetheless, T-cell exhaustion, toxicity, and suppressive microenvironment limit their efficacy in solid tumors. Recently, we characterized a novel subset of tumor-infiltrating CD4+ T-cells expressing the FcγRI receptor (Rasoulouniriana et al, 2019). Herein we detail the engineering of a novel receptor, based on the FcγRI structure, which is retrovirally transduced into PBMCs (both CD4 and CD8 T-cells). These cells, named SolidT cells, can target tumor cells using antibody intermediates. They show effective and specific cytotoxicity only when an appropriate antibody is added. Only target-bound antibodies activate these cells, while free antibodies are internalized without activation. Their cytotoxic activity is correlated to target protein density, therefore targeting tumor cells with high antigen density while sparing normal cells with low or no expression. This activation mechanism prevents premature exhaustion. Furthermore, during ADCC these cells secrete attenuated cytokine levels compared to CAR-T, thereby enhancing their safety profile. These cells eradicate established melanoma tumors, infiltrate the tumor microenvironment and facilitate host immune cell recruitment in immunocompetent mice. In NSG mice, they infiltrate, persist, and eradicate tumors. As opposed to CAR therapies, which require changing the receptor across different types of cancer, our engineered T-cells remain the same throughout tumor types, while only the injected antibody changes. As such, can be adapted to treat a wide range of solid cancers without changing the manufacturing program. Overall, SolidT cells are capable of binding tumor cells with high affinity, while preserving the cytotoxic specificity only to cells expressing a high density of tumor-associated antigens. Citation Format: Diana Rasoulouniriana, Nadine Santana-Magal, Amit Gutwillig, Leen Farhat-Younis, Hana Shpilt, Shahar Dotan, Noam Pilpel, Peleg Rider, Yaron Carmi. A modified FcγRI expressing-T cell, SolidT, enables antibody-mediated cytotoxicity to overcome the limitations of CAR-T cell therapy against solid tumors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4075.